The therapeutic options for prostate cancer are currently limited to prostatectomy or radiation for cure of localized disease and hormone therapy for palliation of advanced cancers. Standard chemotherapy is largely ineffective in this disease. Novel therapeutic approaches are therefore needed. The retinoids (natural and synthetic derivatives of vitamin A), have emerged in the last decade as the premier class of cancer chemopreventive agents, and have been studied extensively in preclinical and clinical investigations. In recent studies, combination of retinoids with alpha- interferon produced impressive responses in patients with advanced epithelial cancers, demonstrating that retinoids may have therapeutic as well as chemopreventive applications. Finally, preclinical data suggest that vitamin D and its derivatives may have anticancer properties, and epidemiological studies have implicated low levels of vitamin D in the progression from latent to clinical prostate cancer. In preliminary work, our group identified differences in the concentration of endogenous retinoids between the normal human prostate, benign prostatic hyperplasia (BPH) and prostate cancer. In addition, we showed that treatment with fenretinide (4-HPR , a synthetic retinoid) reduced the incidence and the volume of ras + myc-induced prostate cancers in mice, and reduced the number of bone metastases in a metastatic variant of this model. Interestingly, fenretinide-treatment caused a several-fold increase in the tissue retinoic aid concentration in both the murine cancers and in human prostates. Finally, we identified the presence of vitamin D receptors in normal and cancerous human prostate tissue and showed that both vitamin D and a nonhypercalcemic analog of vitamin D (EB 1089) inhibited the growth of the human prostate cancer cell line LNCaP. Furthermore, the combination of vitamin D and 9-cis retinoic acid acted synergistically to inhibit growth in this cell line. Our project is focused on developing a biological therapy for prostate cancer and has preclinical and clinical components. We will continue to study endogenous retinoid metabolism in normal and cancerous human prostates, analyze vitamin D/retinoid combinations in vitro, and use animal models to study new retinoids as well as retinoid/interferon and retinoid/vitamin D combinations in vivo. Molecular pathways following the administration of retinoids and of retinoid/vitamin D combinations will be tested in human prostate cancer cell lines and human prostate stromal cell lines using a subtractive hybridization technique. Clinical phase I/II studies will be conducted to assess the effects of retinoids and of retinoid combinations in different stages of prostate cancer. The clinical studies will be tailored to incorporate information from the preclinical animal testing concerning the optimal drug combination and the optimal timing of therapy.